Objective. To provide preliminary data regarding the efficacy and tolerability of the omega-3 fatty acids (omega-3FA) docosahexaenoic acid (DMA) and eicosapentaenoic acid (EPA) in adolescents with major depression (MOD). Rationale. Evidence links central monoamine dysfunction, neurocellular alterations, and immune system dysregulation with MDD. Omega-3FA have been found to have powerful modulatory effects on central monoaminergic activity, are essential structural and functional components of neurons and glia, are effective anti-inflammatory agents, and may be effective in adult mood disorders. A body of epidemiological and neurobiological findings link omega-3FA and MDD. These related observations provide the basis for the proposed study. Hypothesis. Omega-3FA treatment is superior to placebo in adolescents with MDD. Methods. Subjects. 40 medically healthy, antidepressant na[unreadable]ve adolescents, ages 12-18, with MDD for at least 8 weeks and a minimum severity score of >40 on the CDRS-R, and onset of first episode > 12 years. Diagnosis. MDD will be established with the K-SADS-PL. Excluded will be current and past: bipolar disorder, schizophrenia, psychosis, autism, pervasive developmental disorder, .and Tourette's disorder; current post traumatic stress disorder, panic disorder, obsessive-compulsive disorder, attention deficit hyperactivity disorder, conduct disorder, eating disorders, and substance related disorders. Study Treatments. Adolescents will be randomized to 10 weeks of double blind treatment with omega3-FA or matching placebo. Dose will be initiated at 1.2mg/d, titrated flexibly every 2 weeks up to a maximum of 3.6g/d. Omega3-FA will be combined EPA/DHA (ratio 2:1). A minimum of two weeks' duration at lower doses will provide the opportunity to assess clinical response at any one dose. Subjects will be followed weekly by a child psychiatrist. Assessments will include determination of MDD (K-SADS), MDD severity (Children's Depression Rating Scale-Revised [CDRS-R]), clinical global improvement (CGI), adverse events/vital signs, suicidal ideation, food intake checklist. Data Analyses. Two primary outcomes will be used to test the hypothesis: MDD severity indexed by CDRS total scores, and a CGI rating of 1 or 2 (Very Much or Much Improved). An intent to treat design will be applied, controlling for background food intake and other pertinent covariates, if appropriate. Significance. Adolescent MDD is associated with serious functional impairments, including suicide, and represents a major public health concern. In spite of its importance, it has been subject to relatively little biological research. This study stands at the confluence of current efforts to improve the treatment of adolescents with MDD and to develop alternative therapeutic approaches for this group. Should results of this pilot study suggest efficacy and tolerability of omega-3FA, we will plan a larger study to provide an adequate test of omega-3FA efficacy in this clinical population.